This project is concerned with the chemotherapy of inoperable metastatic melanoma by the selective localization of cytotoxic and radioactive agents in malignant melanocytes. The approach used is based on the fact that malignant melanocytes contain a very active specialized, exploitable metabolic pathway, the tyrosine to melanin reaction. The tyrosine to melanin pathway is catalyzed by the enzyme tyrosinase which is attached to a cytoplasmic organelle, the melanosome. The conversion of tyrosine and DOPA to melanin is an irreversible reaction in which the final product, melanin, is fixed in the cell with little or no metabolic turnover; this permits the incorporation of cytotoxic, radioactive or alkylating chemicals into melanin, which remains in the malignant melanocyte. The substrates and inhibitors of tyrosinase selectively localize in melanocytes because only malignant melanocytes contain high levels of tyrosinase.